tbuckley/cabot-search huggingface dataset:
Reference genome assemblies reveal the origin and evolution of allohexaploid oat
Authors: Yuanying Peng, Honghai Yan, Laichun Guo, Cao Deng, Chunlong Wang, Yubo Wang, Lipeng Kang, Pingping Zhou, Kaiquan Yu, Xiaolong Dong, Xiaomeng Liu, Zongyi Sun, Yun Peng, Jun Zhao, Di Deng, Yinghong Xu, Ying Li, Qiantao Jiang, Yan Li, Liming Wei, Jirui Wang, Jian Ma, Ming Hao, Wei Li, Houyang Kang, Zhengsong Peng, Dengcai Liu, Jizeng Jia, Youliang Zheng, Tao Ma, Yuming Wei, Fei Lu, Changzhong Ren
Journal: Nature Genetics (2022)

Common oat (Avena sativa) is an important cereal crop serving as a valuable source of forage and human food. Although reference genomes of many important crops have been generated, such work in oat has lagged behind, primarily owing to its large, repeat-rich polyploid genome. Here, using Oxford Nanopore ultralong sequencing and Hi-C technologies, we have generated a reference-quality genome assembly of hulless common oat, comprising 21 pseudomolecules with a total length of 10.76 Gb and contig N50 of 75.27 Mb. We also produced genome assemblies for diploid and tetraploid Avena ancestors, which enabled the identification of oat subgenomes and provided insights into oat chromosomal evolution. The origin of hexaploid oat is inferred from whole-genome sequencing, chloroplast genomes and transcriptome assemblies of different Avena species. These findings and the high-quality reference genomes presented here will facilitate the full use of crop genetic resources to accelerate oat improvement.
High-throughput techniques enable advances in the roles of DNA and RNA secondary structures in transcriptional and post-transcriptional gene regulation
Authors: Ilias Georgakopoulos-Soares, Candace S. Y. Chan, Nadav Ahituv, Martin Hemberg
Journal: Genome biology (2022)

Abstract The most stable structure of DNA is the canonical right-handed double helix termed B DNA. However, certain environments and sequence motifs favor alternative conformations, termed non-canonical secondary structures. The roles of DNA and RNA secondary structures in transcriptional regulation remain incompletely understood. However, advances in high-throughput assays have enabled genome wide characterization of some secondary structures. Here, we describe their regulatory functions in promoters and 3’UTRs, providing insights into key mechanisms through which they regulate gene expression. We discuss their implication in human disease, and how advances in molecular technologies and emerging high-throughput experimental methods could provide additional insights.
A ROS‐Responsive Liposomal Composite Hydrogel Integrating Improved Mitochondrial Function and Pro‐Angiogenesis for Efficient Treatment of Myocardial Infarction
Authors: Zhi Zheng, Cai Lei, Hongbing Liu, Mingchao Jiang, Zongtao Zhou, Yuqi Zhao, Cui‐Yun Yu, Hua Wei
Journal: Advanced Healthcare Materials (2022)

Abstract Mitochondrial dysfunction of cardiomyocytes (CMs) has been identified as a significant pathogenesis of early myocardial infarction (MI). However, only a few agents or strategies have been developed to improve mitochondrial dysfunction for the effective MI treatment. Herein, a reactive oxygen species (ROS)‐responsive PAMB‐G‐TK/4‐arm‐PEG‐SG hydrogel is developed for localized drug‐loaded liposome delivery. Notably, the liposomes contain both elamipretide (SS‐31) and sphingosine‐1‐phosphate (S1P), where SS‐31 acts as an inhibitor of mitochondrial oxidative damage and S1P as a signaling molecule for activating angiogenesis. Liposome‐encapsulated PAMB‐G‐TK/4‐arm‐PEG‐SG hydrogels demonstrate myocardium‐like mechanical strength and electrical conductivity, and ROS‐sensitive release of SS‐31 and S1P‐loaded liposomes. Further liposomal release of SS‐31, which can target cytochrome c in the mitochondrial inner membrane of damaged CMs, inhibits pathological ROS production, improving mitochondrial dysfunction. Meanwhile, S1P released from the liposome induces endothelial cell angiogenesis by activating the S1PR1/PI3K/Akt pathway. In a rat MI model, the resulting liposomal composite hydrogel improves cardiac function by scavenging excess ROS, improving mitochondrial dysfunction, and promoting angiogenesis. This study reports for the first time a liposomal composite hydrogel that can directly target mitochondria of damaged CMs for a feedback‐regulated release of encapsulated liposomes to consume the overproduced pathological ROS for improved CM activity and enhanced MI treatment.
Performance of Early Capillary Refill Time Measurement on Outcomes in Cardiogenic Shock: An Observational, Prospective Multicentric Study
Authors: Hamid Merdji, Anais Curtiaud, Antoine Aheto, Antoine Studer, Veli-Pekka Harjola, Alexandra Monnier, Kevin Duarte, Nicolas Girerd, Marion Kibler, Hafid Ait-Oufella, Julie Helms, Alexandre Mebazaa, Bruno Levy, Antoine Kimmoun, Ferhat Meziani
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Identification of cardiogenic shock severity is a critical step to adapt the management level upon admission. Peripheral tissue perfusion signs, simple and reliable markers of tissue hypoperfusion have never been extensively assessed during cardiogenic shock. Objectives: To assess the correlation of capillary refill time values with 90-day mortality in cardiogenic shock patients or the need for venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. Also to assess the correlation between capillary refill time and hemodynamic parameters. Methods: All consecutive patients with cardiogenic shock admitted to the intensive care unit of two tertiary teaching hospitals were included in a prospective observational study. Macro-hemodynamic parameters (such as heart rate, blood pressure, left ventricular ejection fraction, and cardiac index) and peripheral tissue perfusion signs, such as capillary refill time on the index fingertip, mottling, and Pv-aCO2 (the difference between partial pressure of CO2 between venous and arterial blood) were recorded at inclusion (0 hour), 6 hours, 12 hours, 24 hours, and 48 hours. The composite primary endpoint was the association between 90-day mortality or the need for VA-ECMO support. Measurements and Main Results: A total of 61 patients were included; at inclusion, simplified acute physiology score II was 64 (52-77) points. The primary endpoint was met by 42% of patients. Capillary refill time values were significantly higher at all time points in nonsurvivors or patients needing VA-ECMO support. In univariate analysis, capillary refill time > 3 seconds at inclusion was associated with 90-day all-cause mortality or VA-ECMO support (hazard ratio, 12.38; 95% confidence interval, 2.91-52.71). Capillary refill time at inclusion was poorly associated with macrocirculatory parameters but significantly correlated with microcirculatory parameters. Further, capillary refill time added incremental value to Cardshock score, with an AUC combination at 0.93. Conclusions: In patients with cardiogenic shock admitted to the ICU, our preliminary data suggest that a prolonged capillary refill time >3 seconds was associated with an early prediction of 90-day mortality or the need for VA-ECMO support.
Venetoclax Plus Gilteritinib for <i>FLT3</i>-Mutated Relapsed/Refractory Acute Myeloid Leukemia
Authors: Naval Daver, Alexander E. Perl, Joseph Maly, Mark Levis, Ellen Ritchie, Mark Litzow, James McCloskey, Catherine C. Smith, Gary Schiller, Terrence Bradley, Ramon V. Tiu, Kiran Naqvi, Monique Dail, Deanna Brackman, Satya Siddani, Jing Wang, Brenda Chyla, Paul Lee, Jessica K. Altman
Journal: Journal of Clinical Oncology (2022)

The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but seldom reduces FLT3mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3mut AML.This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria.Sixty-one patients were enrolled (n = 56 FLT3mut); 64% (n = 36 of 56) of FLT3mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3mut patients was 10.0 months.The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.
The medical expert: time for a re-think?
Authors: Lucy Hanington
Journal: BMJ (2022)

Medical expert opinion continues to play a critical role in a range of criminal, civil, coronial, and regulatory processes.Such opinion can determine, for example, whether or not the Crown Prosecution Service pursues a conviction for gross negligence manslaughter following an incident or error that leads to the death of a patient.It can also, more broadly, dictate the standards to which doctors are held.In the Family Courts, medical opinion is relied upon in relation to decisions where the lives and wellbeing of children are at stake.Medical expert work is undoubtedly important for patients, families, and society as a whole.It can lead to changes that improve patient safety and ensure that justice is done.However, it can also lead to loss of a doctor's career or liberty.If an expert gets it wrong, everyone loses.Legal processes are traumatic for doctors, patients, and families.
Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study
Authors: Matthew M. Heeney, Miguel R. Abboud, Jessie Githanga, Baba P. D. Inusa, Julie Kanter, Alan D. Michelson, Videlis Nduba, Victor Musiime, Mohini Apte, Adlette Inati, Amar M. Taksande, Marielle Andersson, Magnus Åstrand, Noha Maklad, Mohammad Niazi, Anders Himmelmann, Anders R. Berggren
Journal: Blood (2022)

The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.
Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers
Authors: Colette Christiansen, Max Tomlinson, Melissa Eliot, Emma Nilsson, Ricardo Costeira, Yujing Xia, Sergio Villicaña, Olatz Mompeo, Philippa Wells, Juan Castillo-Fernandez, Louis Potier, Marie-Claude Vohl, Andre Tchernof, Julia El-Sayed Moustafa, Cristina Menni, Claire J. Steves, Karl Kelsey, Charlotte Ling, Elin Grundberg, Kerrin S. Small, Jordana T. Bell
Journal: Genome Medicine (2022)

Abstract Background There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers of the identified signals, as well as their potential functional roles. Methods Epigenome-wide association analyses were carried out to determine visceral fat mass-associated differentially methylated positions (VF-DMPs) in SAT samples from 538 TwinsUK participants. Validation and replication were performed in 333 individuals from 3 independent cohorts. To assess functional impacts of the VF-DMPs, the association between VF and gene expression was determined at the genes annotated to the VF-DMPs and an association analysis was carried out to determine whether methylation at the VF-DMPs is associated with gene expression. Further epigenetic analyses were carried out to compare methylation levels at the VF-DMPs as the response variables and a range of different metabolic health phenotypes including android:gynoid fat ratio (AGR), lipids, blood metabolomic profiles, insulin resistance, T2D and dietary intake variables. The results from all analyses were integrated to identify signals that exhibit altered SAT function and have strong relevance to metabolic health. Results We identified 1181 CpG positions in 788 genes to be differentially methylated with VF (VF-DMPs) with significant enrichment in the insulin signalling pathway. Follow-up cross-omic analysis of VF-DMPs integrating genetics, gene expression, metabolomics, diet, and metabolic traits highlighted VF-DMPs located in 9 genes with strong relevance to metabolic disease mechanisms, with replication of signals in FASN , SREBF1 , TAGLN2 , PC and CFAP410 . PC methylation showed evidence for mediating effects of diet on VF. FASN DNA methylation exhibited putative causal effects on VF that were also strongly associated with insulin resistance and methylation levels in FASN better classified insulin resistance (AUC=0.91) than BMI or VF alone. Conclusions Our findings help characterise the adiposity-associated methylation signature of SAT, with insights for metabolic disease risk.
Single dose of budesonide/formoterol turbuhaler compared to salbutamol pMDI for speed of bronchodilator onset in asthma: a randomised cross-over trial
Authors: Nethmi Kearns, Mathew Williams, Pepa Bruce, Melissa Black, Ciléin Kearns, Jenny Sparks, Irene Braithwaite, Mark Weatherall, Richard Beasley
Journal: Thorax (2022)

To compare bronchodilator response after to salbutamol and budesonide/formoterol in adults with stable asthma.
Longitudinal phenotypic aging metrics in the Baltimore Longitudinal Study of Aging
Authors: Pei-Lun Kuo, Jennifer A. Schrack, Morgan E. Levine, Michelle D. Shardell, Eleanor M. Simonsick, Chee W. Chia, Ann Zenobia Moore, Toshiko Tanaka, Yang An, Ajoy Karikkineth, Majd AlGhatrif, Palchamy Elango, Linda M. Zukley, Josephine M. Egan, Rafael de Cabo, Susan M. Resnick, Luigi Ferrucci
Journal: Nature Aging (2022)

Abstract To define metrics of phenotypic aging, it is essential to identify biological and environmental factors that influence the pace of aging. Previous attempts to develop aging metrics were hampered by cross-sectional designs and/or focused on younger populations. In the Baltimore Longitudinal Study of Aging (BLSA), we collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration/neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging and demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity and shorter survival. These associations are more robust compared with the use of phenotypic and epigenetic measurements at a single time point. Estimation of these metrics required repeated measures of multiple phenotypes over time but may uniquely facilitate the identification of mechanisms driving phenotypic aging and subsequent age-related functional decline.
Reproducible measurable residual disease detection by multiparametric flow cytometry in acute myeloid leukemia
Authors: Maximilian A. Röhnert, Michael Kramer, Jonas Schadt, Philipp Ensel, Christian Thiede, Stefan W. Krause, Veit Bücklein, Jörg Hoffmann, Sonia Jaramillo, Richard F. Schlenk, Christoph Röllig, Martin Bornhäuser, Nicholas McCarthy, Sylvie Freeman, Uta Oelschlägel, Malte von Bonin
Journal: Leukemia (2022)

Abstract Measurable residual disease (MRD) detected by multiparametric flow cytometry (MFC) is associated with unfavorable outcome in patients with AML. A simple, broadly applicable eight-color panel was implemented and analyzed utilizing a hierarchical gating strategy with fixed gates to develop a clear-cut LAIP-based DfN approach. In total, 32 subpopulations with aberrant phenotypes with/without expression of markers of immaturity were monitored in 246 AML patients after completion of induction chemotherapy. Reference values were established utilizing 90 leukemia-free controls. Overall, 73% of patients achieved a response by cytomorphology. In responders, the overall survival was shorter for MRD pos patients (HR 3.8, p = 0.006). Overall survival of MRD neg non-responders was comparable to MRD neg responders. The inter-rater-reliability for MRD detection was high with a Krippendorffs α of 0.860. The mean time requirement for MRD analyses at follow-up was very short with 04:31 minutes. The proposed one-tube MFC approach for detection of MRD allows a high level of standardization leading to a promising inter-observer-reliability with a fast turnover. MRD defined by this strategy provides relevant prognostic information and establishes aberrancies outside of cell populations with markers of immaturity as an independent risk feature. Our results imply that this strategy may provide the base for multicentric immunophenotypic MRD assessment.
Mutual regulation between N6-methyladenosine (m6A) modification and circular RNAs in cancer: impacts on therapeutic resistance
Authors: Hong Lin, Yuxi Wang, Pinghan Wang, Fangyi Long, Ting Wang
Journal: Molecular Cancer (2022)

Abstract The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying mechanisms of therapeutic resistance may provide new strategies for overcoming cancer resistance. N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotes, and is involved in the regulation of RNA splicing, translation, transport, degradation, stability and processing, thus affecting several physiological processes and cancer progression. As a novel type of multifunctional non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been demonstrated to play vital roles in anticancer therapy. Currently, accumulating studies have revealed the mutual regulation of m6A modification and circRNAs, and their interaction can further influence the sensitivity of cancer treatment. In this review, we mainly summarized the recent advances of m6A modification and circRNAs in the modulation of cancer therapeutic resistance, as well as their interplay and potential mechanisms, providing promising insights and future directions in reversal of therapeutic resistance in cancer.
Prevention of venous thromboembolic events in patients with lower leg immobilization after trauma: Systematic review and network meta-analysis with meta-epsidemiological approach
Authors: D. Douillet, C. Chapelle, E. Ollier, P. Mismetti, P.-M. Roy, S. Laporte
Journal: PLoS Medicine (2022)

Background Lower limb trauma requiring immobilization is a significant contributor to overall venous thromboembolism (VTE) burden. The clinical effectiveness of thromboprophylaxis for this indication and the optimal agent strategy are still a matter of debate. Our main objective was to assess the efficacy of pharmacological thromboprophylaxis to prevent VTE in patients with isolated temporary lower limb immobilization after trauma. We aimed to estimate and compare the clinical efficacy and the safety of the different thromboprophylactic treatments to determine the best strategy. Methods and findings We conducted a systematic review and a Bayesian network meta-analysis (NMA) including all available randomized trials comparing a pharmacological thromboprophylactic treatment to placebo or to no treatment in patients with leg immobilization after trauma. We searched Medline, Embase, and Web of Science until July 2021. Only RCT or observational studies with analysis of confounding factors including adult patients requiring temporary immobilization for an isolated lower limb injury treated conservatively or surgically and assessing pharmacological thromboprophylactic agents or placebo or no treatment were eligible for inclusion. The primary endpoint was the incidence of major VTE (proximal deep vein thrombosis, symptomatic VTE, and pulmonary embolism-related death). We extracted data according to Preferred Reporting Items for Systematic Reviews and Meta-analyses for NMA and appraised selected trials with the Cochrane review handbook. Fourteen studies were included (8,198 patients). Compared to the control group, rivaroxaban, fondaparinux, and low molecular weight heparins were associated with a significant risk reduction of major VTE with an odds ratio of 0.02 (95% credible interval (CrI) 0.00 to 0.19), 0.22 (95% CrI 0.06 to 0.65), and 0.32 (95% CrI 0.15 to 0.56), respectively. No increase of the major bleeding risk was observed with either treatment. Rivaroxaban has the highest likelihood of being ranked top in terms of efficacy and net clinical benefit. The main limitation is that the network had as many indirect comparisons as direct comparisons. Conclusions This NMA confirms the favorable benefit/risk ratio of thromboprophylaxis for patients with leg immobilization after trauma with the highest level of evidence for rivaroxaban. Trial registration PROSPERO CRD42021257669 .